Myelodysplasia and transgene inactivation in X-CGD-γ retroviral gene therapy: The usual suspects and new players

X-linked chronic granulomatous disease (X-CGD) is an inborn error of immunity in which phagocytic cells are unable to generate sufficient reactive oxygen species (ROS) to fight bacterial and fungal infections due to mutations in the CYBB gene encoding the gp91phox subunit of the NADPH oxidase complex. Hematopoietic stem cell (HSC) gene therapy is now a promising therapeutic option for this disorder. Several clinical trials have reported clear clinical benefits but also highlighted the difficulties in obtaining sustained correction of neutrophils over time. Sadly, early clinical trials using spleen focus-forming virus (SFFV)-derived γ-retroviral vectors were overshadowed by the high incidence of insertional mutagenesis driving the emergence of myelodysplasia.